Despite decades of efforts in the cancer therapies, cancer remains a huge public health burden. Surgery and radiotherapy are quite successful in treating primary tumors. However, once a cancer has disseminated to distant sites, chemotherapy is often required to treat the disease. Cytotoxic agents have played a critical role in modern cancer therapy. However, they usually induce substantial toxicity in normal tissues. The principle for treatment of cancer has changed. Cytotoxic drugs are losing their dominance in the chemotherapy world and targeted therapies are being developed with the aim of more specifically targeting cancer cells. Targeted cancer therapies are a relatively new class of agents with selectivity for targets implicated in tumor growth. They have demonstrated impressive efficacy with much less toxicity than cytotoxic agents.
Protein kinases are a family of enzymes that regulate a wide variety of cellular processes, including cell growth, cell proliferation, cell differentiation and metabolism. The protein kinases communicate cell growth signals through sequential chemical modification of pathway partners. Therefore, pharmacologic inhibition of any kinase on a given signal transduction cascade would theoretically block communication along the entire pathway. In addition, it is known that protein kinases play a role in disease states and disorders, for example, kinase mutation mutation and/or overexpression are frequently characterized in cancers, resulting in hyperactivated activity that often correlates with uncontrolled cell growth. For that reason, protein kinases represent potential targets for therapeutic inhibition. [1]. Cancer Stem Cells (CSC) is a subpopulation of cells within a variety of tumor types with a tumorigenic potential that is lacking in the rest of the cells within these tumors. There is mounting evidence that such cells exist in almost all tumor types. CSC give rise to the differentiated cells that form the bulk of the tumor mass and phenotypically characterize the disease. Cancer stem cells have been demonstrated to be fundamentally responsible for carcinogenesis, cancer metastasis, and cancer reoccurrence. In many tumors, CSC and their differentiated progeny appear to have markedly different biologic characteristics. Conventional therapies that target mature tumor cells may lead to clinical improvement, but are unlikely to be curative unless CSCs are also targeted. Relevant targets unique to the rare cancer stem cells may be missed if clinical activity is judged solely by criteria that reflect the effects of treatment on the bulk of the cancer.
We have recently shown that the compounds in this invention inhibit kinases and kill cancer stem cells, demonstrating that kinases are important targets for killing or inhibiting cancer stem cells. These kinases important for CSCs are collectively referred to CSCPK hereafter. Our results provide a method of targeting cancer stem cells with CSCPK inhibitors.
PDGFRα is a receptor tyrosine kinase (RTK) that is activated after binding to its ligand, PDGF, which contributes to cell proliferation, angiogenesis, and apoptosis. It belongs to class III receptor tyrosine kinase family and are related to the CFS-1 receptor/c-fms and the stem cell growth factor/c-kit proto-oncogene family. PDGFRα pathway is active in early fetal development and reactivated in many cancers, such as hepatocellular cancer (HCC), head and neck cancer, brain tumors, gastrointestinal tumors, skin cancer, prostate cancer, ovarian cancer, breast cancer, sarcoma, and leukemia [2-15]. In addition, PDGFRα activation has recently been shown to play a key role in bone metastasis of prostate cancer [16, 17]. Furthermore, PDGFRα-p70S6K pathway has been shown to be essential for angiogenesis in vivo [18]. Specifically targeting PDGFRα using monoclonal antibody has been shown to lead to significant reduction in tumor cell proliferation and survival while being a relatively non-toxic treatment [11]. Therefore, PDGFRα represents a target for developing targeted chemotherapy against broad spectrum of cancers with less toxicity.
Other than cancer, it has been well demonstrated that chromosomal rearrangements activate PDGFRα by fusion to FIP1L1, causing idiopathic hypereosinophilic syndrome [5]. In addition, activation of PDGFRα by promoter polymorphisms has linked to neural tube defects including spina bifida, which has been verified by mouse mutant model [19]. PDGFRα activation has also been linked with fibrosis [20-23]. For that reason, PDGFRα represents a potential target for anti-fibrotic therapy.